The present invention relates essentially to a process for the production of nanocapsules with cross-linked protein-based walls, to the nanocapsules thereby obtained and to cosmetic, pharmaceutical or food compositions in which they are present.
It is known that the encapsulation of active substances is very important either for protecting the active principle or for permitting a slow or delayed release of the active principle in the organism.
It has been proposed to encapsulate the active principles in liposomes, the latter being an interesting galenical form view their very good affinity with the cell membranes, their very good biocompatibility and their submicron size.
However, these structures have numerous limitations, to see even major disadvantages, which can be summarized in the following four points:
A poor encapsulation yield: liposomes can contain or transport different types of molecules, namely hydrophilic, lipophilic and amphiphilic molecules. However, the encapsulation yields are very low in all cases, which, coupled with the problem of diffusion of the active principles, further reduces the efficacy of the liposomes and in many cases does not permit consideration of their use in therapeutic applications. PA1 A poor reproducibility of the liposome preparations when they are to be produced on the industrial scale. PA1 Instability in vitro: this can manifest itself in various ways, namely chemical instability of the lipids, instability of the size of the liposomes, instability of their structure, formation of aggregates, release of the encapsulated active principles, etc. PA1 Instability in vivo: the influence of biological fluids on the liposomes very often increases their membrane permeabilities. Depending on the administration route used, the liposomes can be in contact with biological fluids as diverse as blood, digestive juices, interstitial fluids etc. and must consequently be capable of withstanding numerous interactions. Now, contact with the majority of biological fluids results in a marked increase in the membrane permeability of the liposomes. By imperfect fusion with the cells, or by contact with salts, enzymes--lipases, phospholipases, acyltransferases--plasma constituents, bile salts or digestive juices, or by simple pH variations, the liposomes can release their active principles into the surrounding medium almost instantaneously.
It has also been proposed to encapsulate the active principles in particles or capsules with dimensions of the order of a few microns. For example, in the document FR-A-2 642 329 identified also by application Ser. No. 89 01221, the same application which forms the basis of priority of U.S. Pat. No. 5,395,620, the Applicant has proposed the preparation of microcapsules with mixed atelo-collagen/glycosaminoglyan walls for encapsulation of the active principle. This method is totally satisfactory except that it does not make it possible to prepare capsules of submicron dimensions, i.e. capsules of nanometer dimensions, called nanoparticles.
Furthermore, nanocapsules with polyacrylamide walls have been proposed, especially by Couvreur et al. in Febs Letters (1977), 84, 323-326, and nanocapsules with polymethyl and polyethyl cyanoacrylate walls have been proposed by the same authors in J. Pharm. Pharmacol. (1979), 31, 331-332. Likewise, it has been proposed in EP-A-0 274 961 to prepare nanocapsules forming colloidal systems based on a vinyl chloride/vinyl acetate copolymer, polyisobutyl cyanoacrylate and poly-(d,l)-lactic acid; in U.S. Pat. No. 4,640,709, BEESTMAN et al. have proposed the preparation, by polycondensation, of small spheres whose membranes consist of a polymeric material such as polyurea, polyamide, polysulfonamide, polyester, polycarbonate and polyurethane.
However, although the latter documents afford capsules of nanometer dimensions, there is a major problem in the fact that these particles generally have poor biocompatibility and poor biodegradation in vitro and in vivo, which may result in the accumulation of a high concentration of particles in certain organs, the toxicity of certain monomers, certain polymerization by-products or certain degradation by-products, and poor protection of the active principles when they are only adsorbed on the surface of the nanoparticles, thereby giving an inadequate delaying effect.